Dodging the checkpoint


Patients with the genetic disorder Fanconi anemia (FA) are prone to cancer due to genomic instability. Mutations in any one of fifteen FA associated genes can lead to abnormal chromosome numbers, though the role of FA proteins in chromosomal segregation is unclear. Grzegorz Nalepa and colleagues at Indiana University found that FA proteins are required for the spindle assemble checkpoint, which prevents duplicate chromosome separation until each chromosome is attached to the spindle apparatus. Individual FA proteins localized to different components of the mitotic apparatus and are required for high-fidelity chromosome segregation during cell division. This study provides insight into how FA pathway disruption leads to an inappropriate number of chromosomes in dividing cells and subsequent cancer development. The accompanying micrograph shows that FA protein C (green) localizes to the centromeres in a mitotic cell (outlined by actin staining (red)) during prometaphase (chromosomes stained blue with DAPI).

Published August 15, 2013, by Corinne Williams

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Fanconi anemia signaling network regulates the spindle assembly checkpoint
Grzegorz Nalepa, Rikki Enzor, Zejin Sun, Christophe Marchal, Su-Jung Park, Yanzhu Yang, Laura Tedeschi, Stephanie Kelich, Helmut Hanenberg, D. Wade Clapp
Grzegorz Nalepa, Rikki Enzor, Zejin Sun, Christophe Marchal, Su-Jung Park, Yanzhu Yang, Laura Tedeschi, Stephanie Kelich, Helmut Hanenberg, D. Wade Clapp
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Research Article Hematology

Fanconi anemia signaling network regulates the spindle assembly checkpoint

Abstract

Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle–dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.

Authors

Grzegorz Nalepa, Rikki Enzor, Zejin Sun, Christophe Marchal, Su-Jung Park, Yanzhu Yang, Laura Tedeschi, Stephanie Kelich, Helmut Hanenberg, D. Wade Clapp

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